scholarly journals Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Lukas Muri ◽  
Emma Ispasanie ◽  
Anna Schubart ◽  
Christine Thorburn ◽  
Natasa Zamurovic ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Pneumococcal Infection ◽  
Alternative Complement Pathway ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Blood Leukocytes ◽  
Complement Components ◽  
Relative Contribution ◽  
Alternative Complement ◽  
Pathway Inhibition

To assess the relative contribution of opsonisation by antibodies, classical and alternative complement pathways to pneumococcal phagocytosis, we analyzed killing of pneumococci by human blood leukocytes collected from vaccine-naïve and PCV13-vaccinated subjects. With serotype 4 pneumococci as model, two different physiologic opsonophagocytosis assays based on either hirudin-anticoagulated whole blood or on washed cells from EDTA-anticoagulated blood reconstituted with active serum, were compared. Pneumococcal killing was measured in the presence of inhibitors targeting the complement components C3, C5, MASP-2, factor B or factor D. The two assay formats yielded highly consistent and comparable results. They highlighted the importance of alternative complement pathway activation for efficient opsonophagocytic killing in blood of vaccine-naïve subjects. In contrast, alternative complement pathway inhibition did not affect pneumococcal killing in PCV13-vaccinated individuals. Independent of amplification by the alternative pathway, even low capsule-specific antibody concentrations were sufficient to efficiently trigger classical pathway mediated opsonophagocytosis. In heat-inactivated or C3-inhibited serum, high concentrations of capsule-specific antibodies were required to trigger complement-independent opsonophagocytosis. Our findings suggest that treatment with alternative complement pathway inhibitors will increase susceptibility for invasive pneumococcal infection in non-immune subjects, but it will not impede pneumococcal clearance in vaccinated individuals.

scholarly journals Continual Low-Level Activation of the Classical Complement Pathway

2001 ◽  
Vol 194 (6) ◽  
pp. 747-756 ◽  
Author(s):  
Anthony P. Manderson ◽  
Matthew C. Pickering ◽  
Marina Botto ◽  
Mark J. Walport ◽  
Christopher R. Parish
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Blood Stasis ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Alternative Complement ◽  
Classical Complement

There is evidence that the classical complement pathway may be activated via a “C1-tickover” mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.

scholarly journals Activation of the guinea pig alternative complement pathway by mouse IgA immune complexes.

1982 ◽  
Vol 155 (1) ◽  
pp. 231-247 ◽  
Author(s):  
G Pfaffenbach ◽  
M E Lamm ◽  
I Gigli
Keyword(s):  
Guinea Pig ◽  
Immune Complexes ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Myeloma Protein ◽  
Pathway Activation ◽  
Alternative Complement ◽  
Iga Immune Complexes

Activation of the complement system by IgA was investigated with immune complexes containing a mouse IgA myeloma protein with specificity for phosphorylcholine linked to bovine serum albumin (PC-BSA). These IgA anti-PC-BSA immune complexes activated the alternative complement pathway in mouse and guinea pig serum, while human complement was not affected. The activation proceeded with consumption of C3 but little or no consumption of C5. C3 did not bind to the IgA immune complexes during complement activation although it did bind covalently to IgG immune complexes. It is suggested that IgA immune complexes do not supply a suitable surface for C3 binding and effective alternative pathway convertase assembly; therefore, cleavage is limited and occurs primarily in the fluid phase. Without C3 binding, C5 cleavage does not occur nor can the alternative pathway activation proceed to the amplification step.

Experimental murine acid aspiration injury is mediated by neutrophils and the alternative complement pathway

1997 ◽  
Vol 83 (4) ◽  
pp. 1090-1095 ◽  
Author(s):  
Martin R. Weiser ◽  
Taine T. V. Pechet ◽  
Julian P. Williams ◽  
Minghe Ma ◽  
Paul S. Frenette ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Alternative Pathway ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Acid Aspiration ◽  
Airway Injury ◽  
Distal Airway ◽  
Alternative Complement

Weiser, Martin R., Taine T. V. Pechet, Julian P. Williams, Minghe Ma, Paul S. Frenette, Francis D. Moore, Lester Kobzik, Richard O. Hines, Denisa D. Wagner, Michael C. Carroll, and Herbert B. Hechtman. Experimental murine acid aspiration injury is mediated by neutrophils and the alternative complement pathway. J. Appl. Physiol. 83(4): 1090–1095, 1997.—Acid aspiration may result in the development of the acute respiratory distress syndrome, an event associated with significant morbidity and mortality. Although once attributed to direct distal airway injury, the pulmonary failure after acid aspiration is more complex and involves an inflammatory injury mediated by complement (C) and polymorphonuclear leukocytes. This study examines the injurious inflammatory cascades that are activated after acid aspiration. The role of neutrophils was defined by immunodepletion before aspiration, which reduced injury by 59%. The injury was not modified in either P- or E-selectin-knockout mice, indicating that these adhesion molecules were not operative. C activation after aspiration was documented with immunochemistry by C3 deposition on injured alveolar pneumocytes. Animals in which C activation was inhibited with soluble C receptor type 1 (sCR1) had a 54% reduction in injury, similar to the level of protection seen in C3-knockout mice (58%). However C4-knockout mice were not protected from injury, indicating that C activation is mediated by the alternative pathway. Finally, an additive effect of neutrophils and C was demonstrated whereby neutropenic animals that were treated with sCR1 showed an 85% reduction in injury. Thus acid aspiration injury is mediated by neutrophils and the alternative C pathway.

scholarly journals Complement 1 Inhibitor Is a Regulator of the Alternative Complement Pathway

2001 ◽  
Vol 194 (11) ◽  
pp. 1609-1616 ◽  
Author(s):  
Haixiang Jiang ◽  
Eric Wagner ◽  
Huamei Zhang ◽  
Michael M. Frank
Keyword(s):  
Human Serum ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Cobra Venom Factor ◽  
Factor B ◽  
Alternative Complement ◽  
Pathway Function ◽  
Cross Competition

We studied complement 1 inhibitor (C1-INH) as an inhibitor of the alternative complement pathway. C1-INH prevented lysis, induced by the alternative complement pathway, of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes in human serum. It inhibited the binding of both factors B and C3 to PNH and rabbit erythrocytes and blocked the ability of factor B to restore alternative-pathway function in factor B–depleted serum. C1-INH did not bind to factors B or D but did bind to immobilized C3b and cobra venom factor (CVF), a C3b analogue. C1-INH prevented factor B from binding to CVF-coated beads and dissociated bound factor B from such beads. Factor B and C1-INH showed cross competition in binding to CVF-coated beads. Factor D cleaved factor B into Bb and Ba in the presence of C3b. Cleavage was markedly inhibited when C3b was preincubated with C1-INH. C1-INH inhibited the formation of CVFBb and decreased the C3 cleavage. Removal of C1-INH from serum, in the presence of Mg-EGTA with an anti–C1-INH immunoabsorbant, markedly increased alternative-pathway lysis. C1-INH interacts with C3b to inhibit binding of factor B to C3b. At physiologic concentrations, it is a downregulator of the alternative pathway convertase.

scholarly journals Activation of the alternative complement pathway with rabbit erythrocytes by circumvention of the regulatory action of endogenous control proteins

1977 ◽  
Vol 146 (1) ◽  
pp. 22-33 ◽  
Author(s):  
DT Fearon ◽  
KF Austen
Keyword(s):  
Alternative Pathway ◽  
Fluid Phase ◽  
Fold Increase ◽  
Alternative Complement Pathway ◽  
Regulatory Proteins ◽  
Low Grade ◽  
Phase Reaction ◽  
Complement Pathway ◽  
Alternative Complement ◽  
Grade Fluid

Cleavage of C3 by the alternative complement pathway occurs in at least two distinct phases: continuous low grade generation of C3b by the interaction of native C3, B, D, and P, and subsequent amplified cleavage of C3 by the interaction of C3b, B, D, and P which forms the amplification convertase, P,C3b,Bb. Transition to C3b-dependent amplification is necessary to achieve substantial C3 cleavage and is normally limited by the combined action of C3b inactivator (C3bINA) and βlH. An activator of the alternative pathway, such as rabbit erythrocytes (E(r)), provides sites that protect bound C3b and P,C3b,Bb from the action of these regulatory proteins and permits C3b deposited by the low grade fluid phase reaction to assemble a membrane-associated amplification convertase which can deposit additional protected C3b. Under conditions in which the control proteins, C3bINA and β1H, almost completely inactivated C3b bound to sheep erythrocytes (E(s)), which does not activate the alternative pathway, the function of C3b bound to E(r) was diminished by less than one-fifth. Further, the P- stabilized amplification convertase on E(r) was 10-fold less sensitive to β1H-mediated decay-dissociation than the convertase on E(s). The addition of E(r) to a regulated mixture of purified C3, B, D, P, C3bINA, and β1H resulted in amplified inactivation of C3 and B by formation of the amplification convertase on E(r) as indicated by its lysis with subsequent exposure to C3-C9. In contrast, E(s) did not advance the low grade fluid phase inactivation of C3 and B to amplified inactivation and the cell was not converted to an intermediate susceptible to lysis by C3- C9. Since E(r) and E(s) did not differ in their inefficient fixation of C3b generated during an unregulated fluid phase reaction, the activating capacity of E(r) must reside in its protection of bound C3b and P, C3b,Bb from the regulatory proteins rather than in enhanced capacity to bind C3b from the fluid phase. When the reaction is limited to low grade fluid phase turnover, introduction of E(r) but not E(s) results in a 100-fold increase in the deposition of C3b, indicating that surface-dependent activation of the alternative pathway is characterized by efficient deposition of C3b on the initiating surface. Thus, the activating surfaces advance the interaction of the alternative pathway proteins to the amplification phase because of the selective inability of the regulatory proteins to deal with their substrates when deposited on these surfaces and results in a specificity that is not necessarily dependent on adaptive immunity.

scholarly journals Opsonization of bacteroides by the alternative complement pathway reconstructed from isolated plasma proteins.

1987 ◽  
Vol 165 (3) ◽  
pp. 777-798 ◽  
Author(s):  
A B Bjornson ◽  
P I Magnafichi ◽  
R D Schreiber ◽  
H S Bjornson
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Time Course ◽  
Alternative Pathway ◽  
Quantitative Difference ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Serum Factors ◽  
Alternative Complement ◽  
Bacterial Surfaces ◽  
The Difference

Opsonization of clinical isolates of B. fragilis and B. thetaiotaomicron with the six isolated proteins of the alternative complement pathway under physiological conditions resulted in considerable C3 deposition on the bacterial surfaces. The time course of C3 deposition was similar to that observed in EGTA-serum; however, the magnitude of C3 deposition was twofold greater in EGTA-serum. Opsonization of the bacteria with the isolated alternative pathway proteins failed to promote adherence, uptake, or killing by polymorphonuclear leukocytes, whereas opsonization of the bacteria with EGTA-serum facilitated these events. The difference in opsonic capacity of isolated proteins and EGTA-serum was not related to the quantitative difference in C3 deposition, because repeated opsonization of the bacteria with isolated proteins resulting in C3 deposition comparable to that observed in EGTA-serum only minimally increased adherence of the bacteria to polymorphonuclear leukocytes. SDS-PAGE and autoradiographic analysis of C3 extracted from bacteria opsonized with isolated proteins or EGTA-serum using methylamine and SDS demonstrated that the predominant form of C3 bound by ester bonds under both sets of conditions was iC3b. A low molecular weight C3 cleavage fragment was detected in extracts from bacteria opsonized with isolated proteins, but it accounted for only a minor fraction of the bound C3. The results of our study demonstrate that the early phase of opsonization involving activation of the alternative pathway by B. fragilis and B. thetaiotaomicron and resultant C3 deposition on the bacterial surfaces does not require auxiliary serum factors, but the effector phase of opsonization of these bacteria involving recognition of bacteria-bound C3 by polymorphonuclear leukocytes and the induction of phagocytosis and intracellular killing is dependent on such factors. Natural IgM antibodies serve as auxiliary factors is opsonization of B. thetaiotaomicron by the alternative pathway, whereas additional serum factors are required for alternative pathway-mediated opsonization of B. fragilis.

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